The overall objective of the proposed project is to study the interaction between environmental and genetic risk factors in the development of Parkinson's disease (PD) with a focus on mechanisms of neurodegeneration. PD is the second most common neurodegenerative disease and is characterized by selective damage to dopaminergic neurons in the substantia nigra. This reduces dopamine levels in the striatum, and symptoms appear when striatal dopamine is decreased by 80%. The etiology of PD remains elusive, although exposure to various environmental toxicants is clearly implicated. In particular, the meperidine-derivative MPTP and the herbicide paraquat (PQ) have been linked to a long term risk of developing symptoms of PD. Additionally, familial forms of the disease have been characterized and a number of mutations, both autosomal dominant and recessive, have been identified. However, an interesting conundrum arose with the identification of patients who are heterozygous for known recessive mutations. Two of the most common genes yielding recessive mutations are parkin, an E3 ubiquitin ligase, and PINK1, a mitochondrial protein acting upstream of parkin. Mitochondrial dynamics represents a potential common pathway, as MPTP and PQ are known to affect mitochondrial activity, and PINK1 and parkin are involved with regulating mitochondrial morphology, key to appropriate mitochondrial function. The studies proposed in this application aim to explore in detail the potential interaction of environmental exposures and heterozygous expression of recessive mutations in PINK1 and parkin. Specifically, this research program aims to 1) Determine whether mice with recessive PD mutations exhibit enhanced nigrostriatal neurotoxicity following exposure to the environmental toxicants MPTP and PQ; 2) Determine if MPTP and PQ affect the expression of mitochondrial fission/fusion proteins in vivo and in vitro, and if this effect is accentuated by recessive mutations; and 3) Explore potential mechanisms mediating the effects of recessive PD mutations and environmental toxicants on mitochondrial fission/fusion proteins. These experiments will utilize both existing and novel animal models of recessive PD in conjunction with the environmental toxicants MPTP and PQ. Additionally, mechanisms of cell damage and mitochondrial dynamics will be assessed using a unique inducible cell culture model of recessive mutations. Careful analysis of fission and fusion proteins in the presence of the toxicants, mutant PINK1 and parkin, and the combination of genes and environmental toxicants will enhance understanding of PD pathogenesis. Finally, identification of other proteins involved in the regulation of mitochondrial dynamics will yield novel targets for the development of new therapeutic strategies. Thus, this research program will contribute greatly to our understanding of the pathogenesis of PD, the role of environmental exposures and the potential gene-environment interaction, providing opportunities for developing novel treatment strategies for this serious disease.